A "Timed" Kiss Is Essential for Reproduction: Lessons from Mammalian Studies

Abstract

Reproduction is associated with the circadian system, primarily as a result of the connectivity between the biological clock in the suprachiasmatic nucleus (SCN) and reproduction-regulating brain regions, such as preoptic area (POA), anteroventral periventricular nucleus (AVPV), and arcuate nucleus (ARC). Networking of the central pacemaker to these hypothalamic brain regions is partly represented by close fiber appositions to specialized neurons, such as kisspeptin and gonadotropin-releasing hormone (GnRH) neurons; accounting for rhythmic release of gonadotropins and sex steroids. Numerous studies have attempted to dissect the neurochemical properties of GnRH neurons, which possess intrinsic oscillatory features through the presence of clock genes to regulate the pulsatile and circadian secretion. However, less attention has been given to kisspeptin, the upstream regulator of GnRH and a potent mediator of reproductive functions including puberty. Kisspeptin exerts its stimulatory effects on GnRH secretion via its cognate Kiss-1R receptor that is co-expressed on GnRH neurons. Emerging studies have found that kisspeptin neurons oscillate on a circadian basis and that these neurons also express clock genes that are thought to regulate its rhythmic activities. Based on the fiber networks between the SCN and reproductive nuclei such as the POA, AVPV, and ARC, it is suggested that interactions among the central biological clock and reproductive neurons ensure optimal reproductive functionality. Within this neuronal circuitry, kisspeptin neuronal system is likely to "time" reproduction in a long term during development and aging, in a medium term to regulate circadian or estrus cycle, and in a short term to regulate pulsatile GnRH secretion.

Keywords: AVPV; GnRH; circadian rhythms; clock genes; kisspeptin; reproduction.

Figure 1

Interactions among the central biological clock and reproductive neurons in the hypothalamic–pituitary–gonadal axis of females. The suprachiasmatic nucleus (SCN), the central biological clock, can be divided into two major subdivisions known as the ventrolateral (vl) SCN, the core, and the dorsomedial (dm) SCN, the shell. The former contains cell bodies of vasoactive intestinal polypeptide (VIP) neurons and the latter contains cell bodies of arginine vasopressin (AVP) neurons. The vlSCN acts as the conductor of rhythmicity and transmits synchronizing cues to the dmSCN. VIP neurons project to gonadotropin-releasing hormone (GnRH) neurons in the preoptic area (POA), whereas AVP neurons project to kisspeptin (Kiss) neurons in the anteroventral periventricular nucleus (AVPV). Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamus (DMH) inhibit the activity of GnRH neurons as well as kisspeptin neurons in the AVPV and arcuate nucleus (ARC). AVPV kisspeptin neuron is also regulated by stimulatory and inhibitory neurotransmitters glutamate and GABA, respectively. GnRH is released at the median eminence (ME) to stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary, which stimulate steroidogenesis and gametogenesis in the ovary. Estradiol (E2) secreted from the ovary gradually increases and rapidly decreases during the estrous cycle [metestrous (M), diestrus (D), proestrus (P), and estrus (E)] in rodents. GnIH and Kiss neurons express estrogen receptor (ER) to convey hormonal information to the reproductive neuronal network. ARC Kiss neurons may function as part of the negative feedback mechanism of E2 on pulsatile GnRH release at the ME. On the other hand, AVPV Kiss neurons may function as the positive feedback mechanism of high E2 concentration on GnRH/LH surge. E2 inhibits GnIH gene expression in the DMH and Kiss gene expression in the ARC but stimulates Kiss gene expression in the AVPV. Kiss and GPR54 are reported to be expressed in gonadotropes, and they are thought to exert synergic effects with GnRH and E2 on LH release (13). Solid lines indicate direct regulation by receptors of signaling molecules, whereas dotted lines indicate possible indirect regulation.